Table 2.

Vascular and inflammatory effects on the nervous system following restricted cranial or thoracic exposure to blast in experimental animals.

Species	Blast exposure	Vascular effects	Inflammatory effects	Other effects/effects of shielding	Reference
Rat	Shock tube, whole body blast (338.9 kPa, 52 ms duration) or local pulmonary blast (440 kPa, 50 ms duration)		Evidence of elevated oxidative stress and antioxidant enzyme defense systems (superoxide anion radical generation, increased malondialdehyde concentration, superoxide dismutase and glutathione activity) in hippocampus of animals in both groups at 3 and 24 h after exposure, mostly returning to normal by 5 days	Swollen neurons, glial reaction, and myelin debris in hippocampus by EM following whole body or local pulmonary blast, deficits in performance on an active avoidance task 3 h after injury, deficits in active avoidance task persisted at 5 days only in rats subjected to whole body blast	(62)
Pig	Local exposure to abdomen or top of skull, blast overpressure generated with air-compressed driven shock tube at levels of approximately 30 kPa in tube, and 14.4 kPa in air outside the abdomen, or 22 kPa in air outside the skull			Following abdominal exposure, maximal peak pressure in brain was 0.5 kPa in brain vs. 15 kPa in abdomen (brain 3% of that in the abdomen), 9 kPa in brain after direct skull exposure	(39)
Rat	Shock tube, 126 and 147 kPa exposures with or without Kevlar vest encasing thorax and part of the abdomen			Kevlar vest prevented widespread fiber degeneration that was prominent in brains of rats not protected by vest during a 126 kPa exposure	(63)
Rat	Shock tube, 358 kPa, duration 10 ms, head only exposure with body armor protection	Intracranial hematomas with brain swelling	GFAP accumulation in hippocampus 24 h after blast, still present at 30 days	Prominent silver staining in deep brain areas, increased GFAP and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) in CSF, body protection increased the threshold for mortality	(64)
Mouse	103 kPa (14.9 psi) whole body blast unprotected, or with chest and abdomen protected (body armor), or with head protected		Evidence of inflammation in brain as judged by bioluminescence imaging of myeloperoxidase (MPO) activity, MPO activation still present in brain 30 days after exposure without body protection	Head protection failed to prevent MPO activation in brain, body protection blocked blast-MPO activity in brain	(65)
Rat	Equivalent of 400 mg TNT detonated at various distances (100–400 kPa), exposed through portal in cabin that limited direct exposure to head	Acutely diffuse subarachnoid hemorrhage, contusions, and capillary damage in the cortex at 200 and 400 kPa exposures, minor/minimal injury at 100 kPa			(30)
Rat	Shock tube, 20.63 psi exposed as whole body blast with chest protection	Vascular endothelial cell growth factor (VEGF) increased in dorsal and ventral hippocampus at 71 days after exposure	IL-6 and IFN-γ levels elevated in amygdala and hippocampus but not prefrontal cortex 71 days after exposure, increased numbers of GFAP immunostained cells in the ventral hippocampus	Changes normalized by environmental enrichment	(66)
Rat	Shock tube utilizing compressed-air or helium, explosives oxyhydrogen, and cyclotrimethylenetrinitramine (RDX), 100–200 kPa, durations ~3–5 ms direct and ~6–7 ms reflected, rats fitted with Kevlar vest to protect the thorax with body protected by steel tube	Dilated blood vessels and hematomas visible grossly immediately after exposure			(31)
Mouse	Shock tube, 68 ± 8 kPa (9.9 ± 1.2 psi) static pressure, 103 kPa (14.9 psi) total pressure, with head or torso shielding			Without shielding multifocal axonal injury primarily in cerebellum/brain stem, corticospinal tract, and optic tract, prolonged behavioral and motor abnormalities including deficits in social recognition, spatial memory, and motor coordination, shielding of torso ameliorated axonal injury and partially protected against behavioral deficits, head protection not associated with any apparent benefits on the severity of axonal degeneration	(67)
Rat	Helium-driven shock tube, 35 psi (positive phase duration approximately 4 ms) applied to the left side of the head with body shielded	Increased BBB permeability suggested by IgG immunostaining at 24 h primarily affecting the contralateral cortex	GFAP, ED1, and Iba-1 immunostaining not prominently increased at 24 h, 72 h, or 2 weeks post-blast although small numbers of reactive microglia within areas of neuronal death	25% mortality due to impact apnea, surviving rats studied at 24 h, 72 h, or 2 weeks post-blast showed multifocal axonal degeneration by silver staining, deep cerebellar and brainstem white matter tracts most heavily affected, mild multifocal neuronal death at 24 and 72 h	(68)
Rat	Cranium only blast injury apparatus (COBIA) delivering blast overpressures generated by detonating 22 caliber cartridges of smokeless powder (450–700 kPa, complex pressure wave > 3 ms duration)	Widespread subarachnoid hemorrhages without cortical contusions or intracerebral or intraventricular hemorrhages, abnormal vascular immunolabeling for IgG in cerebellum, thalamus, and entorhinal cortex 1–7 days after blast exposure		Increased amyloid precursor protein, FluoroJade C and caspase-3 staining	(34)
Rat	Shock tube, 20.63 psi exposed as whole body blast with chest protection		51 days post-blast exposure elevated CRP, MCP-1, toll receptor 9, and GFAP in amygdala, prefrontal cortex, ventral and dorsal hippocampus, VEGF receptor fetal liver kinase 1 (FLK-1), claudin-5 and aquaporin-4 elevated in ventral hippocampus, FLK-1 and aquaporin-4 elevated in dorsal hippocampus and amygdala	Levels reduced by treatment with the non-steroidal anti-inflammatory drug minocycline for four consecutive days after blast exposure	(69)
Rat	Shock tube, one or five 138 kPa exposures with chest protection		GFAP immunostaining increased in hippocampus at 2 days post-exposure in single injured and at 22 days post-exposure in multiply injured		(70)
Pig	Shock tube, 24–37 or 40–52 psi in protective body armor	CSF VEGF elevated at 6 h, 72 h, and 2 weeks post-blast exposure but normal at 24 h, CSF von Willebrand factor increased at 6, 24, and 72 h but normal at 2 weeks			(71)
Ferrets	Shock tube, 98–837 kPa (durations from 2.1–14.1 ms) focused on head with thoracic and abdominal protection	Varying degrees of subdural, subarachnoid, and intracerebral hemorrhage, all worse at higher blast intensities		Apnea and death	(32)
Pig	Shock tube, blasts directed to unprotected head with lungs, and thorax protected using ballistic vests (110–740 kPa peak incident overpressure with durations from 1.3–6.9 ms)			Immediate apnea in 5 of 20 animals, no gross bleeding in brain, intracranial pressures ranged from 80–390 kPa which were lower than shock tube reflected pressures of 300–2830 kPa	(72)
Rat	Shock tube, head only, or chest only exposure (65, 110, 160, and 185 kPa)	Blood pressure in internal carotid artery rose 2–10 times physiological pressure of 14 kPa for ~2 ms after blast, rise correlated with level of blast	1 week post-exposure infiltration of CD68 + macrophages into brain	Pressure rise with chest only exposure 30% higher than head only, infiltration of CD68 + macrophages into the brain following chest exposure only	(73)
Rat	Tabletop shock tube, 31.47, 50.72, 72.05, and 90.1 psi (duration ~2 ms) delivered with thoracic and abdominal protection	Gross intracerebral hemorrhages 50.72 psi and above, immediate mortality with extensive intracranial bleeding at exposure to 90.1 psi and above	Increased number of GFAP expressing astrocytes and activated microglia in corpus callosum		(74)
Rat	Rifle primer-driven shock tube, primary blast at 145, 232, and 323 kPa (positive phase durations 14.2–55.8 μs), lungs protected by Kevlar vest	BBB disruption detected by IgG extravasation detected immunohistochemically with 232 and 323 kPa exposures at 24 and 48 h, small lesions scattered throughout brain, number and size of lesions correlated with peak overpressure level, despite laterally directed blast, equal numbers of lesions found in each hemisphere			(75)
Rat	Shock tube, 79 psi (1 ms duration) with or without shielding		Polymorphonuclear leukocytes (PMN) and lymphocytes infiltrated brain parenchyma within 1 h post-blast, GFAP, cyclo-oxygenase-2, interleukin-1β, and TNF-α present by 1 h and still detectable at 3 weeks post-injury, pro-inflammatory high mobility group box-1 protein detectable at 3 weeks	Greater 24 h infiltration of PMN and lymphocytes in non-shielded animals	(76)
Rat	Custom built blast simulator, 14 psi, repeated three times at 1.5 min intervals, body protected by a holding tube with head positioned perpendicular to nozzle of blast simulator		24 h after exposure increased 4-hydroxynonenal, (4-HNE) in the dorsal hippocampal commissure and forceps major corpus callosum, 7 days post-exposure increased GFAP expression in most brain regions	Antioxidant treatment (2,4-disulfonyl α-phenyl-tert- butyl nitrone and N-acetyl-cysteine) beginning 1 h after blast exposure reduced 4-HNE, and GFAP expression as well as upregulated amyloid precursor protein and neurofilament-68 expression	(77)
Rat	Live explosives (22 caliber cartridge of smoke-less powder), thorax-only blast injury apparatus (TOBIA, 451 kPa, duration 2 ms) or jugular-only blast injury apparatus (JOBIA, blast pressure applied to a jugular port, 59 mm Hg, ~400 ms duration pressure in jugular vein)	Immunolabeling 24 h after injury by TOBIA showed upregulation of TNF-α, ED-1, Sur1, and GFAP in veins or perivenular tissues and microvessels throughout brain	Upregulation of TNF-α, ED-1, Sur1, and GFAP	Blast injury induced by TOBIA caused apnea and diffuse bilateral hemorrhagic injury to lungs, perivenular effects by TOBIA prevented by ligating jugular vein and reproduced by JOBIA	(78)
Rabbit	TNT paper equivalent 600 mg, 638.2 kPa at 6.5 cm vertical distance from head, positive pressure duration 0.18 ms, body enclosed in wooden box with only head protruding	Frequent intracranial hemorrhages, increased BBB permeability based on Evans blue content in brain beginning at 6 h after injury, reaching peak at 48 h and remaining elevated at 3 days (last time point studied)	Elevated TNF-α and IL-8 peaking at 12–18 h	Transient apnea, bradycardia, and increased blood pressure immediately after exposure, treatment with hyperbaric oxygen reduced increases in BBB permeability and lowered levels of TNF-α and IL-8	(36)
Rat	Shock tube, five exposures administered as progressively higher exposures from 15.54–19.41 psi (107.14–133.83 kPa, durations 9.01–10.6 ms) at rate of 1 per 30 min with chest protection	2 days post-exposure elevation in one or more brain regions of VEGF and von Willebrand factor (vWF)	Two days post-exposure elevation in one or more brain regions of 4-HNE, hypoxia-inducible factor 1 α (HIF1α), aquaporin-4, integrin α6, Gal-1, MIP1, chemokine receptor 5 (CCR5), toll-like receptor 9, p38 mitogen-activated protein kinase and osteopontin, microglia and astrocyte markers (CD53/OX44), and GFAP increased	Transient depression of heart rate and oxygen saturation, 2 days post-exposure elevation of metallopeptidase inhibitor 1 (TIMP1), and matrix metalloproteinase 8 (MMP8)	(79)
Rat	Head-directed blast from a 27 caliber cartridge detonated 2 cm from head		Increased levels of IL-1β in hippocampus and thalamus and TNF-α in hippocampus at 6 h after injury, increased Iba-1 expressing microglia at 6 h and 30 days		(80)
Rat	Focal head exposure from bench-top blast wave generator (peak overpressure 885 kPa, rise time 4.7 ms)		8 h after exposure protein levels of erythropoietin, endothelial integrins, ICAM and sVCAM, and MCP-1 elevated in cortex, six inflammatory genes examined by qRT-PCR increased (complement C3, chemokines MCP5, MCP1, MCP3, I-PAC, and MDC)		(81)
Rat	Open-field electric detonator with 100 mg dinonyl-ortho- phthalate and 250 mg trimethylene-trinitroamine (equivalent of 400 mg TNT), rats fixed inside an aluminum shielded box with a 1 cm hole allowing frontal, parietal, and occipital parts of head exposed, detonator 7.5 cm from the center of the hole	Diffuse subarachnoid and intraparenchymal hemorrhage acutely	Brain nitric oxide (NO) and expression and activity of inducible nitric oxide synthase (iNOS) increased 2–24 h after exposure	Treatment with emodin, a possible inflammatory inhibitor, reduced pathology as well as NO and iNOS levels	(82)
Rat	Shock tube, blast wave directed to right side of skull with a polyvinyl chloride shield protecting rest of body, (peak incident overpressure of ~15 psi)	Increased BBB permeability at 6 h following blast as judged by Evans blue extravasation, increased VE-cadherin and occludin in brain, increased PKC isozymes in brain microvessels		Treatment with bryostatin-1, a PKC isozyme modulator decreased BBB breakdown	(83, 84)
Rat	Shock tube driven head-directed blast wave (66.5 to 94.0 psi, duration 10 ms)			Head directed exposure induced centrally mediated apnea acutely	(85)